1. Field of the Invention
The present invention relates to process for the preparation of a cyclopropylacetylene derivative and a cyclopropylacrylic acid derivative which is an intermediate in synthesis of the cyclopropylacetylene derivative. A cyclopropylacetylene derivative produced by the present invention is useful as an intermediate in synthesis for a compound having a cyclopropane skeleton, for example a benzoxazinone derivative (L-743726), which has an anti-HIV activity (Tetrahedron Letters, vol. 36, p. 8937 (1995)) and the like.
2. Discussion of the Related Art
Recently, many physiologically active substances having a cyclopropane skeleton have been discovered. Well known methods of producing a cyclopropylacetylene derivative, for example cyclopropylacetylene, which is useful for an intermediate in synthesis for these compounds, are:
(1) a method in which cyclopropyl methyl ketone is reacted with phosphorus pentachloride in carbon tetrachloride to produce 1,1-dichloro-1-cyclopropylethane, which is dehydrochlorinated by potassium tert-butoxide (Synthesis, p. 703, (1972) and Journal of Organic Chemistry, vol. 41, p. 1237 (1976)); PA1 (2) a method in which 5-chloropentyne is reacted with n-butyl lithium in cyclohexane (Tetrahedron Letters, vol. 36, p. 8937 (1995)); and PA1 (3) a method in which cyclopropanecarboxaldehyde is reacted with carbon tetrabromide in the presence of triphenylphosphine by Wittig reaction to produce 1,1-dibromo-2-cyclopropylethylene, followed by the reaction with methyllithium (Tetrahedron, vol. 45, p. 363 (1989)). PA1 which comprises reacting a cyclopropylacrylic acid derivative represented by the following formula (I): ##STR5## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the same meanings as defined above, R.sup.6 represents a hydrogen atom, an alkyl group which may have a substituent, a carboxyl group or a protected carboxyl group, and R.sup.7 represents a hydrogen atom or a protecting group for a carboxyl group (hereinafter simply referred to as cyclopropylacrylic acid derivative (I)), with a halogenating agent to obtain a halogenocyclopropylpropionic acid derivative represented by the following formula (II): ##STR6## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 have the same meanings as defined above, and X and Y each represents a halogen atom (hereinafter simply referred to as halogenocyclopropylpropionic acid derivative (II)), and reacting the halogenocyclopropylpropionic acid derivative (II) with a base.
However, the method (1) affords many by-products and a yield of the target compound is low, the method (2) requires use of expensive n-butyl lithium or lithium diisopropylamide and the method (3) produces large amount of triphenylphosphine oxide as a by-product which is troublesome to separate. Therefore, these methods are hard to evaluate as being industrially useful methods for cyclopropylacetylene.
On the other hand, as methods to construct a cyclopropane skeleton, known are: a Simmons-Smith method in which olef in is reacted with carbene that is produced by the reaction of 1,1-dihalo-compound and zinc copper alloy (New Experimental Chemistry Lecture Course, vol. 14, p. 84 (1977)); a method in which sulfur ylid is reacted with olefin (New Experimental Chemistry Lecture Course, vol. 14, p. 91 (1977)); a method using a decomposition reaction of an azo compound (New Experimental Chemistry Lecture Course, vol. 14, p. 82 (1977)); and an intramolecular cyclization reaction of a butanoic acid derivative having a leaving group at .gamma.-position (New Experimental Chemistry Lecture Course, vol. 14, p. 93 (1977)).
As methods to construct an acetylene structure, known are: a coupling reaction of a metal acetylide (a metallic salt of acetylene) with a compound having a leaving group (New Experimental Chemistry Lecture Course, vol. 14, p. 271 (1977)); a reaction of a halogeno compound with a base (The fourth edition: Experimental Chemistry Lecture Course, vol. 19, p. 298 (1992)); a reaction of a nitrogen-containing compound such as hydrazone with a mercury compound or a base (The fourth edition: Experimental Chemistry Lecture Course, vol. 19, p. 310 (1992)); and an isomerization of an acetylene compound by a base (The fourth edition: Experimental Chemistry Lecture Course, vol. 19, p. 312 (1992)).
However, if a method mentioned above to construct a cyclopropane skeleton is applied to synthesis of a cyclopropylacetylene derivative, there arise problems that a side-reaction between carbene and acetylene occurs and many stages in a process are required in construction of a acetylene structure.
In addition to the above mentioned methods, it is known that an aldehyde derivative having a naphthalene ring is transformed by way of an acrylic acid derivative, to a vinyl derivative and to an acetylene derivative (Comptes Rendus, vol. 229, p. 660 (1949) and Justus Liebigs Annalen der Chemie, vol. 387, p.257 (1912)). But a cyclopropane ring has a high distortion, at which point the ring is different from a naphtalene ring, to cause a ring-opening reaction by electrophile (Journal of Synthetic Organic Chemistry, Japan, vol. 41, p. 22 (1983)). Therefore, it is thought that if such a method is applied to synthesis of a cyclopropylacetylene derivative, a side reaction which is represented by a ring-opening of a cyclopropane ring by bromine has a high probability to occur (Angewandte Chemie International Edition in English, vol. 15, p. 762 (1976)).
As a method of production of a cyclopropylacrylic acid derivative, known are the following methods: (4) a method in which cyclopropanecarboxaldehyde is reacted with malonic acid using pyridine as a solvent and a base (Tetrahedron: Asymmetry, vol. 8, p. 883 (1997) and Journal of the American Chemical Society, vol. 73, p. 3831 (1951)); (5) a method in which cyclopropanecarboxaldehyde is reacted with phosphonic acid derivative in the presence of a base to synthesize cyclopropylacrylate ester (Journal of Organic Chemistry, vol. 59, p. 6476 (1994), Journal of Organic Chemistry, vol. 55, p. 3088 (1990), Journal of the American Chemical Society, vol. 91, p. 6432 (1969) and Journal of the American Chemical Society, vol. 90, p. 3769 (1968)); and (6) an addition reaction of an acetylenecarboxylate with dicyclopropyl copper derivative prepared from cyclopropyl halide (Journal of Organic Chemistry, vol. 41, p. 3629 (1976)).
However, it is difficult that these methods are applied to an industrial production of a cyclopropylacrylic acid derivative by following reasons; according to the method (4), since pyridine is used as a solvent, removal and recovery of pyridine are problematic in an industrial scale of synthesis and moreover, a reaction requires a long time of period; according to the method (5), it is necessary to use expensive n-butyllithium or sodium hydride; and according to the method (6), it is necessary to employ many stages in synthesis of a starting material.
Under such circumstances, desired is a method in which a cyclopropylacetylene derivative and a cyclopropylacrylic acid derivative, which is an intermediate in synthesis of the cyclopropylacetylene derivative, can be produced in good yields under moderate conditions and thereby advantageously on an industrial scale.